Center News

Fighting the fatal reactions that no one tells you about

March 21, 2002
Dr. Danny Shen loads extract of a blood specimen onto a liquid chromatograph/mass spectrometer.

Dr. Danny Shen loads extract of a blood specimen onto a liquid chromatograph/mass spectrometer, which analyzes the levels of metabolites. Metabolite levels reflect activity of enzymes in the intestine and liver, indicating how much drug actually gets into the bloodstream.

Photo by Michelle Hruby

Cholesterol-lowering drugs might save you from a fatal heart attack. Take them with grapefruit juice, though, and you could die from a condition that causes severe muscle breakdown.

Such adverse drug interactions appear in fine print on pill bottles of all kinds and accompany pharmacists' instructions when they dispense prescriptions.

Yet there are likely many adverse drug interactions caused by dietary supplements and herbal remedies that your pharmacist doesn't know about and drug manufacturers are unlikely to consider, said Dr. Danny Shen of the Clinical Research Division.

Shen plans to address this problem in his lab.

As the recent recipient of a $1.2 million grant from the National Center for Complementary and Alternative Medicine (NCCAM), he and colleague Dr. Karen Syrjala will embark on studies of potential adverse interactions between St. John's wort, a popular herbal antidepressant, and two pain medications (oxycodone and fentanyl) commonly prescribed for cancer patients.

NCCAM is a relatively new branch of the National Institutes of Health dedicated to research on alternative, or non-Western, therapies and treatments.

No testing requirement

Although an estimated 60 million Americans use herbal remedies, the government does not require that such preparations be tested for adverse drug reactions including interactions with prescription drugs.

The Dietary Supplement Health and Education Act, passed by Congress in 1994, put dietary supplements in a different category from other drugs, triggering a flood of new over-the-counter products whose effects on other drugs are largely unknown.

Recently, though, several studies have demonstrated that some herbal preparations do interfere with the action of other drugs, including two with serious health implications. Researchers found that St. John's wort reduces the effectiveness of cyclosporine, an immunosuppressive drug used in stem-cell and solid organ transplantation, and indinavir, a protease inhibitor used to treat HIV infection.

Those findings, predicts Shen, "are just the tip of the iceberg" for St. John's wort, whose efficacy has been tested in randomized, controlled clinical trials.

"There will be more examples of adverse interactions to come," he said. "Unfortunately, because Congress has disallowed the FDA to regulate dietary supplements as drugs, very little testing of this kind has been done. Manufacturers of herbal products are unlikely to put warnings of drug interactions on their product labels unless the FDA can prove a safety problem and makes such a label caution a requirement."

As a researcher on the pharmacology of pain medications and a professor of pharmacy at the University of Washington, Shen is most concerned with how St. John's wort might affect the action of drugs like oxycodone (the active compound in drugs like Percoset and OxyContin) and fentanyl (active ingredient in Duragesic patch and Actiq), which are commonly prescribed to relieve pain in cancer patients.

Both of these analgesics are members of a class of drugs known as opioids that work by activating opioid receptors, which modulate the transmission of painful signals through the body and its perception by our brain.

Overprescribing

The studies with cyclosporine and indinavir showed that daily use of St. John's wort lowered circulating levels of these drugs by more than 50 percent. Such reduction in levels of oxycodone and fentanyl could have a significant impact on their effectiveness in managing pain-and could also lead doctors to overprescribe these potent analgesics.

For example, in standard pain treatment, a patient receives gradually increasing doses of opioid until the medication provides pain relief. If this patient took St. John's wort along with an opioid, then subsequently stopped treatment with St. John's wort, it is possible that the patient could be overdosed.

Based on similarities in the metabolism of the opioids, cyclopsorine and indinavir, Shen believes there is a high probability that St. John's wort will interfere with the action of the analgesics he's testing.

"For the cyclosporine and indinavir studies, it was clear that the lower levels of circulating drug had something to do with how much of the drug was absorbed into the blood stream," he said.

"For both drugs, under normal circumstances, not all is absorbed in the blood - a lot is biotransformed, or metabolized, by a drug-metabolizing enzyme called CYP3A4. The gut lining and the liver have a number of these drug-metabolizing enzymes, probably to protect the body from toxic substances in the diet. What that means is when you take a drug, your body's response is to try to get rid of it and to a certain extent, the body succeeds."

St. John's wort increases the amount and activity of CYP3A4, resulting in even lower levels of drugs getting into the bloodstream and lessening the medication's desired effect.

"CYP3A4 metabolizes more than 50 percent of the drugs we use," Shen said. "This means that interactions of drugs with St. John's wort may be very common."

A second focus of Shen's grant will be to examine whether St. John's wort interferes with the ability of opioid analgesics to cross the blood-brain barrier. Like the detoxifying enzymes that line the body's cavities, the blood-brain barrier has evolved to protect the brain from the entry of harmful substances. Drugs designed to act on the brain, such as analgesics, must cross this barrier.

A study conducted in late 2000 found that St. John's wort enhances the activity of a transporter protein called MDR1 in the intestinal lining whose job is to prevent certain drugs from being absorbed into the bloodstream after they are ingested. Some cancerous cells can overproduce this protein, making them resistant to anticancer drugs, Because this transporter protein is also normally found in the blood-brain barrier, Shen worries that St. John's wort could increase this protein at the blood-brain barrier and would then prevent oxycodone and fentanyl from reaching the brain.

"If this turns out to be the case, combined with the CYP3A4 effect, it would really be a case of double jeopardy," he said. "Patients who are prescribed analgesics might not get any pain relief. Nobody has looked at this problem."

Different reactions

In previous research, Syrjala and Shen have demonstrated that individuals react differently with respect to pain relief and side effects.

St. John's wort, in combination with opioids, may aggravate or alleviate some effects like sedation, constipation, memory or motor skills, independent of its effect on pain. "St. John's wort has a clean record on its own, with no reported side effects and good results in treating mild depression based on randomized controlled trials," he said. "But based on the pharmacological profile of St. John's wort, it could aggravate the side effects of opioids. We want to make sure it doesn't cause more problems than it relieves."

Shen's intent is that these laboratory studies will soon have a direct impact on patient care.

"I think it's our job to alert people to the possibility of drug interactions," he said. "With increasing use of herbal and dietary supplements, we have a glut of things to look out for now."


Why determine the effects of St. John's wort on analgesics?

An assessment of the effects of the popular herbal antidepressant called St. John's wort on analgesics is critical because depression and pain are common among cancer patients, said Dr. Karen Syrjala of the Clinical Research Division.

"About 40 percent of cancer patients have pain at any one time, but I believe all cancer patients experience pain at some point, mostly from their treatment, not from their disease," she said. "This pain is relatively easy to treat effectively, provided we don't have to contend with unknown interactions with other drugs."

Depression among cancer patients is difficult to quantify but likely ranges between 20 and 30 percent, Syrjala said.

"In our transplant patients, whom we evaluate from pre-transplant to five years post-transplant, the rate for what we call major depression holds pretty steady at 9 to 12 percent, which is more than twice the rate seen in the general population," she said. "Another 20 percent of transplant patients experience what we would consider stress-related depression and those are the people more likely to benefit from St. John's wort. Of course pain makes depression worse."

Syrjala said that as many as half of cancer patients take some kind of herbal supplement, but up to 80 percent of patients don't tell their doctors what they are taking and doctors are only now beginning to ask.

"So we don't really know how many cancer patients take St. John's wort, but we can assume the number is high since this is one of the most popular herbal supplements," she said.

Fred Hutchinson Cancer Research Center is a world leader in research to prevent, detect and treat cancer and other life-threatening diseases.